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Syntillas Release Ca²⁺ at a Site Different from the Microdomain Where Exocytosis Occurs in Mouse Chromaffin Cells

Ronghua ZhuGe ^* , Valerie DeCrescenzo ^*, Vincenzo Sorrentino , F. Anthony Lai , Richard A. Tuft ^* , Lawrence M. Lifshitz ^* , Jose R. Lemos ^*, Corey Smith ^¶, Kevin E. Fogarty ^*  and John V. Walsh, Jr. ^*

^* Department of Physiology, and Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Dipartimento di Neuroscienze, Università di Siena, 53100 Siena, Italy; Wales Heart Research Institute, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom; and ^¶ Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970

Correspondence: Address reprint requests to John V. Walsh, Dept. of Physiology, University of Massachusetts Medical School, Worcester, MA 01655. Tel.: 508-856-3360; Fax: 508-856-1840; E-mail: john.walsh{at}umassmed.edu.

Spontaneous, short-lived, focal cytosolic Ca²⁺ transients were found for the first time and characterized in freshly dissociated chromaffin cells from mouse. Produced by release of Ca²⁺ from intracellular stores and mediated by type 2 and perhaps type 3 ryanodine receptors (RyRs), these transients are quantitatively similar in magnitude and duration to Ca²⁺ syntillas in terminals of hypothalamic neurons, suggesting that Ca²⁺ syntillas are found in a variety of excitable, exocytotic cells. However, unlike hypothalamic nerve terminals, chromaffin cells do not display syntilla activation by depolarization of the plasma membrane, nor do they have type 1 RyRs. It is widely thought that focal Ca²⁺ transients cause "spontaneous" exocytosis, although there is no direct evidence for this view. Hence, we monitored catecholamine release amperometrically while simultaneously imaging Ca²⁺ syntillas, the first such simultaneous measurements. Syntillas failed to produce exocytotic events; and, conversely, spontaneous exocytotic events were not preceded by syntillas. Therefore, we suggest that a spontaneous syntilla, at least in chromaffin cells, releases Ca²⁺ into a cytosolic microdomain distinct from the microdomains containing docked, primed vesicles. Ryanodine (100 µM) reduced the frequency of Ca²⁺ syntillas by an order of magnitude but did not alter the frequency of spontaneous amperometric events, suggesting that syntillas are not involved in steps preparatory to spontaneous exocytosis. Surprisingly, ryanodine also increased the total charge of individual amperometric events by 27%, indicating that intracellular Ca²⁺ stores can regulate quantal size.

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